Strong epidemiological evidence exists to suggest that cigarette smoke is deleterious to female reproductive health and fetal development. We postulate that an important mechanism through which cigarette smoke adversely affects the female reproductive system involves direct damage to the ovaries, expressed as accelerated atresia of oocytes and altered ovarian steroid metabolism. In the proposed investigations we will test this hypothesis by determining (1) the levels of cotinine and cadmium, induction of aryl hydrocarbon hydroxylase (AHH) activity and the presence of DNA adducts in the ovarian and uterine tissues, (2) the time course of estrous cycle changes, (3) the rate of follicular atresia, and (4) aromatase activity and steroid levels in ovarian tissue of control, sham- treated and smoke-exposed (mainstream and sidestream) mice. Our preliminary studies show that the average length of the estrous cycle and the relative frequency of the estrous stages in C57B1 mice given long-term exposure to mainstream cigarette smoke is significantly altered, thus suggesting the suitability of mouse as the animal model. Mice will be exposed twice daily to fresh mainstream or sidestream smoke from the University of Kentucky reference cigarettes (2R1), in a nose-only exposure system under controlled smoke generation and exposure conditions. The exposures will be monitored by measuring the total particulate matter (TPM) intake, blood carboxyhemoglobin levels, and the induction of pulmonary AHH activity in experimental animals. Estrous cycle changes will be determined by an examination of the vaginal cytology. Follicular atresia will be evaluated by oocyte counts in serial sections of the ovaries. Ovarian aromatase activity will be measured using 3H- androstenedione as substrate. Plasma and ovarian levels of estrogen and progesterone will be assayed using standard radioimmunoassays. These studies will demonstrate whether or not inhaled cigarette smoke constituents are transferred to the reproductive organs and whether cigarette smoke exposure causes ovotoxicity as reflected by the presence of DNA adducts, accelerated loss of oocytes, and altered steroid metabolism in the ovaries.